This project represents a continuation of closely coordinated clinical and basic laboratory investigations of multiple myeloma (MM) and related plasma cell dyscrasias (PCD). The specific goals of the individual projects are as follows. (1) Clinical and immunochemical studies of PCD will elucidate the pathogenesis and pathophysiology of PCD; characterize monoclonal immunoglobulins (MIg) with respect to their antibody activities and those properties which relate to specific pathophysiological manifestations in individual cases, e.g., amyloidosis, polyneuropathy and lipodystrophies; and investigate new methods of treatment of myeloma, macroglobulinemia and amyloidosis. (2) Studies of the assembly and hapten binding of myeloma proteins will determine the primary, secondary and, if possible, tertiary structures of human MIg, particularly those with known antibody specificities; develop mouse hybridomas secreting MIg with the same specificity as a human M protein (IgGGAR) and compare their primary and secondary structures; and further investigate the pattern of chain assembly of human and mouse MIg. (3) Screening of human myeloma proteins for anticarbohydrate activity will identify and characterize MIg with anticarbohydrate activity for the purpose of performing detailed analyses of primary, secondary and tertiary structures; and attempt to relate the defined specificities to possible pathogenic mechanisms in specific patients whose MIg display these antibody activities. (4) Determination of patterns of cell differentiation in PCD will characterize the markers on peripheral blood lymphocytes and plasma cells in PCD and define the changes in markers during the terminal stages of B cell differentiation; study the effect of antigens on the idiotype expression in vitro by cells of those cases of PCD with defined antigen specificity; and study the dynamics of histocompatibility antigens in B-cell leukemias, lymphomas and IgM PCD and its functional significance with regard to differentiation.